The long-term goal of these studies is to understand how drugs modulate the cochlear amplifier. The mammalian cochlea is a mechanical structure that is tuned along its length tonotopically. Outer hair cells (OHCs) within the cochlea undergo high-speed length changes in sync with sound vibrations, adding energy via a positive feedback loop. This is called the cochlear amplifier and provides exquisite hearing sensitivity and frequency selectivity. OHC motility is based upon the highly organized biomechanical structure of the cell's lateral wall, which contains a plasma membrane, a cytoskeleton, and motor proteins. The specific objective of this project is to determine whether drugs that change OHC lateral wall biomechanics in vitro will modulate cochlear mechanics in vivo. There are three categories of drugs that will be tested: amphipathic drugs which change membrane tension by causing cell membranes to bend, drugs that affect the actin-spectrin cytoskeleton and change cell stiffness, and drugs that directly block the electromotility motor. The compound action potential (CAP), distortion product otoacoustic emissions (DPOAEs), and the medial olivocochlear (MOC) reflex will be monitored to assess cochlear function in anesthetized guinea pigs before and during the administration of these drugs. Because OHCs are the most sensitive cell in the cochlea to noise exposure, drugs that change OHC biomechanics may also modulate noise-induced hearing loss. This will be tested in the guinea pig model. Finally, the effect of these drugs on sound conditioning will be assessed. This is a protective process whereby long-term exposure to moderate-level sound can reduce permanent threshold shifts from subsequent high-level noise exposure. Overall, these studies are designed to understand how OHCs transmit forces within the cochlea and the mechanisms behind sound conditioning. Clinically, they will improve our comprehension of the generation of otoacoustic emissions, as well as the role of the efferent nerves on the cochlear amplifier in health and disease. Additionally, these studies may lead to therapeutic interventions for noise-induced hearing loss and tinnitus.